Abstract
The cellular serine protease TMPRSS2, a member of the type II transmembrane serine protease (TTSP) family, cleaves and activates the hemagglutinin of influenza A viruses (FLUAV) in cell culture and is essential for spread of diverse FLUAV in mice. Non-human primates (NHP), in particular rhesus and cynomolgus macaques, serve as animal models for influenza and experimental FLUAV infection of common marmosets has recently also been reported. However, it is currently unknown whether the NHP orthologues of human TMPRSS2 cleave and activate FLUAV hemagglutinin and contribute to viral spread in respiratory tissue. Here, we cloned and functionally analyzed the macaque and marmoset orthologues of human TMPRSS2. In addition, we analyzed the macaque orthologues of human TMPRSS4 and HAT, which also belong to the TTSP family. We found that all NHP orthologues of human TMPRSS2, TMPRSS4 and HAT cleave and activate HA upon directed expression and provide evidence that endogenous TMPRSS2 is expressed in the respiratory epithelium of rhesus macaques. Finally, we demonstrate that a serine protease inhibitor active against TMPRSS2 suppresses FLUAV spread in precision-cut lung slices of human, macaque and marmoset origin. These results indicate that FLUAV depends on serine protease activity for spread in diverse NHP and in humans. Moreover, our findings suggest that macaques and marmosets may serve as models to study FLUAV activation by TMPRSS2 in human patients.
Highlights
Influenza A virus (FLUAV) infection is a major source of global morbidity and mortality
All PCR products were cloned into plasmid pCAGGS and the encoded protein sequences were found to be identical to those deposited in Genbank
Directed and endogenous expression of TMPRSS2 in cell culture was shown to activate FLUAV HA [12,14,15] and the protease was found to be expressed in receptorpositive cells in the human aerodigestive tract [13]
Summary
Influenza A virus (FLUAV) infection is a major source of global morbidity and mortality. The annual influenza epidemics claim up to 500,000 lives, with children, the elderly and patients with compromised immune system being mainly affected. Available vaccines protect only against seasonal influenza and need to be reformulated annually while antivirals are the only defense against pandemic FLUAV. Antiviral drugs targeting the viral proteins neuraminidase (NA) and M2 are available but their antiviral activity can be compromised by resistance development [4]. The use of M2 inhibitors is not recommended due to high frequency of viral resistance. Novel antiviral strategies are required to provide protection against FLUAV. Host cell proteins essential for viral spread but dispensable for survival of the cell are attractive targets for novel approaches to antiviral intervention, since their blockade might be associated with a high barrier against viral resistance [5]
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